Cryptococcosis is a life-threatening disease caused by the ubiquitous, encapsulated fungus, Cryptococcus neoformans. Although individuals with T cell deficiencies are the most susceptible group for this disease, normal individuals have been reported to have cryptococcosis. Without T cell function, the currently available antifungal drugs do not cure the disease. Consequently, it is desirable to develop immunomodulatory or immunoreplacement therapies; however, without sufficient understanding of the protective and nonprotective aspects of the hosts resistance mechanisms, it is impossible to develop successful immunotherapies. It is clear that certain aspects of the anticryptococcal cell-mediated immune (CMI) responses are protective; whereas others are not. Using an immunocompetent mouse model, we have found that two different immunogens induce anticryptococcal CMI responses that are detectable by delayed- type hypersensitivity (DTH), but one immunogen induces a profile of two functionally different activated CD4+ T cells and protection; whereas the other immunogen induces a different set of activated T cells including both CD4+ and CD8+ T cells and no protection. We propose to exploit these models of two different immune states to define the protective and nonprotective leukocytes, cytokines, chemokines and chemokine receptors. We have developed a murine model in which we implant gelatin sponges into immunized mice, and once the immune response is established then we inject the sponges with either saline (control) or specific antigen (DTH-reaction site). Over a period of 24 h after antigen injection, the DTH-reactive sponges display leukocyte infiltrates, cytokines and chemokines characteristic of a DTH reaction. We propose that the cellular and chemical events at this reaction site are similar to events at the site of infection in an immune host. Consequently by comparing the events occurring in DTH-reactive sponges in mice immunized to get a protective T cell profile with similar sponges in mice immunized to get a nonprotective T cell profile then we will be able to understand which combinations) of leukocytes, leukocyte receptors, cytokines, chemokines and chemokine receptors is necessary for protection and which of the components are associated with the nonprotective CMI response. Through the use of neutralization studies with antibodies and knockout mouse experiments, we plan to elucidate the interactions and codependence of the various components needed for protection against C neoformans. The information obtained from these studies will be useful for designing effective immunoreplacement and immunomodulatory therapies.